Both experimental and epidemiological data suggest that there is a wide range of infectiousness among patients with tuberculosis. Although much research has focused on the virulence of the organism, little is known of the host determinants of infectiousness. A novel Cough Aerosol Sampling System (CASS) can isolate and quantify (viable airborne Mycobacterium tuberculosis from individual patients with pulmonary tuberculosis. We hypothesize that the production of viable aerosols of M. tuberculosis determined by this method is correlated with infectiousness. Our central hypothesis is that most of the variability of infectiousness in tuberculosis is explained by non-immunological host factors including the duration of antimycobacterial therapy with drugs to which the organism is susceptible, the strength and frequency of coughing, and the physicochemical properties of the sputum. The first specific aim is to correlate viability assessed by the air sampling method used in the CASS and infectiousness using the mouse and guinea pig models. The second aim is to determine if the infectiousness of tuberculosis decreases rapidly with appropriate anti-mycobacterial therapy. The third aim is to assess whether cough strength and frequency are associated with the quantity of viable aerosol. The fourth aim is to determine if infectiousness is associated with physicochemical properties of sputum. These data may alter clinical practice and public health control measures. Changes in tuberculous aerosol viability associated with drug therapy may provide insight into the basic biology of the mycobacterial cell wall. Similarly, the rapid changes in cough strength and frequency may suggest mechanisms in the pathophysiology of cough. Verifying the correlation between quantitative aerosol cultures and infectiousness using animal models may validate the use of the cough aerosol sampling system at the bedside. Data obtained from patients with tuberculosis may in turn validate the use of animal models of infection. This approach may open a new field of investigation of the host determinants of infectiousness, which could be extended to other respiratory infectious agents in the future.